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T-cell engagers provide an off-the-shelf approach to redirect endogenous T cells toward tumor cells. However, bispecific formats are constrained by intra- and interpatient antigen heterogeneity, which can limit therapeutic efficacy. In this review, we examine trispecific T-cell engagers (TriTEs) as an emerging strategy to address this limitation\u00a0by simultaneously targeting multiple tumor-associated antigens. We discuss principles guiding antigen selection in glioblastoma, summarize available preclinical evidence supporting multispecific engagement, and outline key design considerations, including molecular architecture, stability, half-life extension, and safety optimization. We further review delivery strategies, such as gene-encoded expression, cellular carriers, and blood\u2013brain barrier modulation, that may improve tumor access and the durability of TriTEs. Together, these considerations position TriTEs as a modular immunotherapy platform relevant to glioblastoma and other heterogeneous solid tumors.<\/jats:p>","DOI":"10.1007\/s00401-026-03063-w","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T09:55:14Z","timestamp":1785750914000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Improving T-cell engager efficacy in glioblastoma with multi-antigen targeting and novel delivery approaches"],"prefix":"10.1007","volume":"152","author":[{"given":"Arushi","family":"Tiwari","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristen D.","family":"Pawlowski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina V.","family":"Balyasnikova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,3]]},"reference":[{"key":"3063_CR1","doi-asserted-by":"publisher","first-page":"50","DOI":"10.4236\/ojpathology.2012.23011","volume":"2","author":"DMD Abech","year":"2012","unstructured":"Abech DMD, Pereira-Lima JFS, Le\u00e3es CGS, Meurer RT, Barbosa-Coutinho LM, Ferreira NP et al (2012) Cell replication and angiogenesis in central nervous system tumors and their relationship with the expression of tissue prolactin and hyperprolactinemia. 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